Structure adaptation in Omicron SARS-CoV-2/hACE2: Biophysical origins of evolutionary driving forces.

Since its emergence, the COVID-19 threat has been sustained by a series of transmission waves initiated by new variants of the SARS-CoV-2 virus. Some of these arise with higher transmissivity and/or increased disease severity. Here, we use molecular dynamics simulations to examine the modulation of the fundamental interactions between the receptor binding domain (RBD) of the spike glycoprotein and the host cell receptor (human angiotensin-converting enzyme 2 [hACE2]) arising from Omicron variant mutations (BA.1 and BA.2) relative to the original wild-type strain. Our key findings are that glycans play a vital role at the RBD···hACE2 interface for the Omicrons, and the interplay between glycans and sequence mutations leads to enhanced binding. We find significant structural differences in the complexes, which overall bring the spike protein and its receptor into closer proximity. These are consistent with and attributed to the higher positive charge on the RBD conferred by BA.1 and BA.2 mutations relative to the wild-type. However, further differences between subvariants BA.1 and BA.2 (which have equivalent RBD charges) are also evident: mutations reduce interdomain interactions between the up chain and its clockwise neighbor chain in particular for the latter, resulting in enhanced flexibility for BA.2. Consequently, we see occurrence of additional close contacts in one replica of BA.2, which include binding to hACE2 by a second RBD in addition to the up chain. Although this motif is not seen in BA.1, we find that the Omicrons can directly/indirectly bind a down-RBD to hACE2 through glycans: the role of the glycan on N90 of hACE2 switches from inhibiting to facilitating the binding to Omicron spike protein via glycan-protein lateral interactions. These structural and electrostatic differences offer further insight into the mechanisms by which viral mutations modulate host cell binding and provide a biophysical basis for evolutionary driving forces.

Phase Behavior of Alkyl Ethoxylate Surfactants in a Dissipative Particle Dynamics Model.

We present a dissipative particle dynamics (DPD) model capable of capturing the liquid state phase behavior of nonionic surfactants from the alkyl ethoxylate (CnEm) family. The model is based upon our recent work [Anderson et al. J. Chem. Phys. 2017, 147, 094503] but adopts tighter control of the molecular structure by setting the bond angles with guidance from molecular dynamics simulations. Changes to the geometry of the surfactants were shown to have little effect on the predicted micelle properties of sampled surfactants, or the water-octanol partition coefficients of small molecules, when compared to the original work. With these modifications the model is capable of reproducing the binary water-surfactant phase behavior of nine surfactants (C8E4, C8E5, C8E6, C10E4, C10E6, C10E8, C12E6, C12E8, and C12E12) with a good degree of accuracy.

Wettability of a Poly(vinylidene fluoride) Surface by a Pure Good Solvent and a Good Solvent/Nonsolvent Mixture: All-Atom Molecular Dynamics Study.

This study investigated the wettability of poly(vinylidene fluoride) (PVDF) surfaces by a good pure solvent and a good solvent/nonsolvent mixture based on all-atom molecular dynamics (MD) simulations. In particular, droplets of pure N-methyl-2-pyrrolidone (NMP) and of mixed NMP/water molecules were brought into contact with both crystalline and amorphous PVDF surfaces. The contact angles of the macroscopic droplets on the crystalline surface were higher and those on the amorphous surface were lower than the experimental values. As the PVDF sheet surface is a mixture of crystalline and amorphous phases, the experimental contact angles being between those on crystalline and amorphous surfaces is reasonable. On the crystalline surface, the decrease in the contact angle with increasing NMP concentration in the droplets can be explained by the increase in the NMP density near the solid-liquid interface. On the amorphous surface, however, the contact angle is strongly affected by the swelling of PVDF by the mixed droplets at high NMP concentrations. The solvation free energy of PVDF in NMP is greater than that in water, suggesting that this may be a driving force of the swelling of the amorphous PVDF. Furthermore, when the Cassie equation for mixed crystalline and amorphous surfaces was assumed, the calculated contact angle corresponded well with the experimental value.

All-atom molecular dynamics study on the non-solvent induced phase separation: Thermodynamics of adding water to poly(vinylidene fluoride)/N-methyl-2-pyrrolidone solution.

The change in the thermodynamics when adding water in poly(vinylidene fluoride) (PVDF)/N-methyl-2-pyrrolidone (NMP) solution is studied from all atom molecular dynamics (MD) simulations. This is done by estimating the free energy of mixing of PVDF/NMP solution with increasing volume fraction of water (ϕw) using an appropriately chosen thermodynamic cycle and the Bennett acceptance ratio method. The MD calculations predict the thermodynamic phase separation point of water/NMP/PVDF to be at ϕw = 0.08, in close agreement with the experimental cloud point measurement (ϕw = 0.05). Examining the enthalpic and entropic components of the free energy of mixing reveals that at low concentrations of water, the enthalpy term has the most significant contribution to the miscibility of the ternary system, whereas at higher concentrations of water, the entropy term dominates. Finally, the free energy of mixing was compared with the Flory-Huggins (FH) free energy of mixing by computing the concentration-dependent interaction parameters from MD simulations. The FH model inadequately predicted the miscibility of the PVDF solution, mainly due to its negligence of the excess entropy of mixing.

Molecular Dynamics Study on Wettability of Poly(vinylidene fluoride) Crystalline and Amorphous Surfaces.

The present study investigates the effect of microscopic structure on the wettability of poly(vinylidene fluoride) (PVDF) surfaces using all-atom molecular dynamics simulations of water droplets brought into contact with both crystal and amorphous PVDF surfaces. For each case, computations were performed using five different droplet diameters, and the corresponding water droplet contact angles θ were obtained. Using the fact that the cosine of these contact angles for both surfaces are inversely proportional to the radius of the droplet contact surface ( rdr( Z0)), the contact angle θ∞ of the macroscopic water droplet was obtained by extrapolating cos θ to 1/ rdr( Z0) = 0. The estimated values of θ∞ on the crystal and amorphous surfaces were 96° and 86°, respectively, showing that the amorphous surface is less hydrophobic than the crystal surface. The contact angle of the crystalline/amorphous mixed surface was estimated using the Cassie equation to be 91°. This value agrees well with experimental measurement of the water contact angle on the PVDF film. Furthermore, the interaction energy, interface structure, and electrostatic potential were analyzed to clarify the reason for the lower hydrophobicity of the amorphous surface. This surface interacts more favorably with water than the crystal surface. Such an interaction reduces the excess free energy (interfacial tension) at the PVDF and water interface and makes the amorphous surface less hydrophobic. The amorphous interfacial region contains more water molecules than the crystal one, and water molecules are oriented toward the PVDF. This interface structure makes water strongly interact with the PVDF.

Effect of Chain Length on the Partition Properties of Poly(ethylene oxide): Comparison between MARTINI Coarse-Grained and Atomistic Models.

The MARTINI coarse-grained beads are parameterized to match the partition coefficients of several organic molecules in different solvents. Here, we test the method when modeling the partitioning properties of poly(ethylene oxide) between solvents of different polarities. We show that, among the existing models, the latest model developed by Lee and co-workers [ Lee , H. ; Pastor , R. W. J. Phys. Chem. B 2011 , 115 , 7830 - 7837 ] is the one that most successfully reproduces the hydration free energy of short oligomers, although it predicts highly negative solvation free energies in octanol and hexane. We develop a new CG model matching the solvation free energy of the monomer in different solvents and propose a simple method to select the Lennard-Jones parameters that reproduce the desired partition coefficients. The model correctly reproduces water/hexane partition properties for oligomers up to 10 monomers but still suffers from a transferability problem for larger molecular weight.

Scaling Behavior of Polymers at Liquid/Liquid Interfaces.

The dynamics of a polymer chain confined in a soft 2D slit formed by two immiscible liquids is studied by means of molecular dynamics simulations. We show that the scaling behavior of a polymer confined between two liquids does not follow that predicted for polymers adsorbed on solid or soft surfaces such as lipid bilayers. Indeed, our results show that in the diffusive regime the polymer behaves like in bulk solution, following the Zimm model, and with the hydrodynamic interactions dominating its dynamics. Although the presence of the interface does not affect the long-time diffusion properties, it has an influence on the dynamics at short time scale, where for low molecular weight polymers the subdiffusive regime almost disappears. Simulations carried out when the liquid interface is sandwiched between two solid walls show that, when the confinement is a few times larger than the blob size, the Rouse dynamics is recovered.

Thermodynamics of linear and star polymers at fluid interfaces.

Performing molecular dynamics simulations on model systems we study the structural changes and thermodynamic stability of polymers of varying topology (linear and star-shaped) at interface between two liquids. We find that homopolymers are attracted to the interface in both good and poor solvent conditions showing that they are surface active molecules even though not amphiphilic. In most cases changing polymer topology had only a minor effect on the desorption free energy. A noticeable dependence on polymer topology is only seen for relatively high molecular weight polymers at interface between two good solvents. Examining separately the enthalpic and entropic components of the desorption free energy suggests that its largest contribution is the decrease in the enthalpic part of interfacial free energy caused by the adsorption of the polymer at the interface. Finally we propose a simple method to qualitatively predict the trend of the interfacial free energy as a function of the polymer molecular weight.